Loss of PACS-2 delays regeneration in DSS-induced colitis but does not affect the ApcMin model of colorectal cancer

Abstract

PACS-2 is a multifunctional sorting protein that mediates cell homeostasis. We recently identified PACS-2 in a functional genome-wide siRNA screen for novel regulators of the metalloproteinase ADAM17, the main sheddase for ligands of the ErbB receptor family. Of note, we showed that Pacs2-/- mice have significantly reduced EGFR activity and proliferative index in the intestinal epithelium. As EGFR signaling is highly mitogenic for intestinal epithelial stem cells, and plays essential roles in intestinal epithelial regeneration and tumor development, we have now examined the role of PACS-2 in these processes. Specifically, we analyzed the role of Pacs2-deficiency in a DSS-induced colitis model as well as in the genetic ApcMin colon cancer model. We now report that loss of PACS-2 delays tissue regeneration after colonic injury with little effect on key inflammatory parameters. We did however not observe any apparent effects on tumor formation driven by excessive proliferative signaling downstream from APC-deficiency. Our findings reveal that the role of PACS-2 in regulating ADAM17-mediated shedding is not an obligate requirement for the epithelium to respond to the strong inflammatory or tumorigenic inducers in the models assessed here.

iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACE

“…Ablation of PACS-2 in cells impairs the cell surface availability of TACE, reducing substrate cleavage ( Dombernowsky et al, 2015 ). However, PACS-2 has a relatively modest impact on TACE biology in vivo ( Dombernowsky et al, 2017 ), suggesting the possibility of unidentified trafficking regulators that may act separately from, or redundantly with, PACS-2.…”

iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACE

“…Our work illustrates iTAP as a physiological rheostat controlling TNF signalling and a novel target for the control of inflammation. (Dombernowsky et al, 2017), suggesting the possibility of unidentified trafficking regulators that may act separately from, or redundantly with, PACS-2.…”

PACS-2 functions in colorectal cancer

“…To answer this question, depletion of pacs2 in mice is a useful experimental model. PACS-2-deficient mice do not develop spontaneous neoplastic lesions in the intestine, and we recently reported that inactivation of one allele of the APC gene (ApcMin) – a commonly used model of human colon cancer – in PACS-2-deficient mice had no apparent consequence for adenoma development [ 3 ].…”